Project Summary Antimicrobial innovation has slowed to a crawl while an epidemic of antimicrobial-resistant infections surges, threatening the public health. The overarching goal of this project is to develop a novel natural product antifungal, selvamicin, targeting drug-resistant fungal infections. This molecule was identified from a symbiotic animal environment. Growing evidence suggests this is a rich and untapped source of novel compounds. More importantly, the molecules from these symbiotic environments exhibit an extremely high rate of both biological activity and animal safety, presumably due to the evolutionary selection of the symbiotic relationship between the antibiotic producing microbe and animal. Consistent with this hypothesis, preliminary data with selvamicin demonstrates promising broad-spectrum activity against drug-resistant fungi in vitro and in pilot animal studies coupled with the absence of a toxicity signal from early cell and whole animal drug exposure studies. The proposed Phase 1 studies will further explore the feasibility for clinical development of this lead antifungal via three IND enabling aims. Aims 1 and 2 will expand preclinical efficacy, pharmacokinetic, and toxicology investigation. Aim 3 will focus on scale up compound production and physiochemical characterization needed for subsequent GLP production required for Phase 2 toxicology analysis and early human studies. The milestones for success will clearly discern the therapeutic potential of selvamicin by defining the the murine PK/PD target in standard FDA utilized models, the safety and therapeutic window for standard end organs, and advance production and chemical analysis toward GLP/GMP capacity for Phase 2 development.